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Synthetic Forms Most Beautiful: Engineering Insights into Self-Organization

Physiology (Bethesda, Md.) 2025年第4期40卷 0-0页

作者： Xu, Zhejing Chang, Chih-Chia Coyle, Scott M. Department of Biochemistry University of Wisconsin-Madison WI United States Integrated Program in Biochemistry Graduate Program University of Wisconsin-Madison WI United States Biophysics Graduate Program University of Wisconsin-Madison WI United States

Reflecting on the diversity of the natural world, Darwin famously observed that "from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved." However, the examples that we are able to observe in nature are a consequence of chance, constrained by selection, drift, and epistasis. Here we explore how the efforts of synthetic biology to build new living systems can expand our understanding of the fundamental design principles that allow life to self-organize biological form, from cellular to organismal levels. We suggest that the ability to impose a length or timescale onto a biological activity is an essential strategy for self-organization in evolved systems and a key design target that is now being realized synthetically at all scales. By learning to integrate these strategies together, we are poised to expand on evolution's success and realize a space of synthetic forms not only beautiful but with diverse applications and transformative potential.

关键词： biological form and function evolution self-organization spatiotemporal control synthetic biology

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O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine (vol 13, 2904, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 2904页

作者： Kim, Kibum Yoo, Hee Chan Kim, Byung Gyu Kim, Sulhee Sung, Yulseung Yoon, Ina Yu, Ya Chun Park, Seung Joon Kim, Jong Hyun Myung, Kyungjae Hwang, Kwang Yeon Kim, Sunghoon Han, Jung Min Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. Yonsei Institute of Pharmaceutical Sciences College of Pharmacy Yonsei University Incheon 21983 South Korea. Center for Genomic Integrity Institute for Basic Science Ulsan 44919 South Korea. Department of Biotechnology College of Life Sciences and Biotechnology Korea University Seoul 02841 South Korea. Department of Biochemistry School of Medicine Catholic University of Daegu Daegu 42472 South Korea. Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. jhan74@yonsei.ac.kr.

All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

关键词： Glycobiology Metabolism Nutrient signalling Post-translational modifications

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Synthesis and Evaluation of Quinolino-Benzoxaboroles as Potential Antimicrobial Agents

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International Journal of Organic Chemistry 2022年第2期12卷 53-63页

作者： Greeshma P. Kumpati Michael J. Williams Srinidhi Mereddy Joseph L. Johnson Shirisha Jonnalagadda Integrated Biosciences Graduate Program University of Minnesota Duluth MN USA Department of Chemistry and Biochemistry University of Minnesota Duluth Duluth MN USA Department of Biology University of Washington Seattle WA USA

Several quinolino-benzoxaborole derivatives have been prepared to start from aminobenzoxaboroles. These derivatives have been evaluated for their anti-cancer activity on human and murine cancer cell lines and based on their relative non-toxicity, these compounds were further evaluated for their antibacterial activity against E. coli, B. subtilis, and M. smegmatis. The synthesized compounds were also evaluated for antifungal activity in C. albicans and C. neoformans.

关键词： Benzoxaboroles Aminobenzoxaboroles Quinolino-Benzoxaboroles Anti-Microbial Agents

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Another wrinkle with age: Aged collagen and intra-peritoneal metastasis of ovarian cancer

Aging and Cancer

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Aging and Cancer 2022年第2期3卷 116-129页

作者： Harper, Elizabeth I. Hilliard, Tyvette S. Sheedy, Emma F. Carey, Preston Wilkinson, Paul Siroky, Michael D. Yang, Jing Agadi, Elizabeth Leonard, Annemarie K. Low, Ethan Liu, Yueying Biragyn, Arya Annunziata, Christina M. Stack, Mary Sharon Department of Chemistry and Biochemistry University of Notre Dame Notre Dame IN United States Harper Cancer Research Institute University of Notre Dame Notre Dame IN United States Integrated Biomedical Sciences Graduate Program University of Notre Dame Notre Dame IN United States National Institute on Aging Bethesda MD United States National Cancer Institute Bethesda MD United States

Background: Age is the most significant risk factor for ovarian cancer (OvCa), the deadliest gynecologic malignancy. Metastasizing OvCa cells adhere to the omentum, a peritoneal structure rich in collagen, adipocytes, and immune cells. Ultrastructural changes in the omentum and the omental collagen matrix with aging have not been evaluated. Aim: The aim of this study was to test the hypothesis that age-related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host. Methods/Results: Young (3–6 months) and aged mice (20–23 months) were used to study the role of aging in metastatic success. Intra-peritoneal (IP) injection of ID8Trp53^–/– OvCa cells showed enhanced IP dissemination in aged versus young mice. In vitro assays using purified collagen demonstrated reduced collagenolysis of aged fibers, as visualized using scanning electron microscopy (SEM) and quantified with a hydroxyproline release assay. Omental tumors in young and aged mice showed similar collagen deposition;however enhanced intra-tumoral collagen remodeling was seen in aged mice probed with a biotinylated collagen hybridizing peptide (CHP). In contrast, second harmonic generation (SHG) microscopy showed significant differences in collagen fiber structure and organization in omental tissue, and SEM demonstrated enhanced omental fenestration in aged omenta. Combined SHG and Alexa Fluor-CHP microscopy in vivo demonstrated that peri-tumoral collagen was remodeled more extensively in young mice. This collagen population represents truly aged host collagen, in contrast to intra-tumoral collagen that is newly synthesized, likely by cancer-associated fibroblasts. Conclusions: Our results demonstrate that tumors in an aged host can grow with minimal collagen remodeling, while tumors in the young host must remodel peri-tumoral collagen to enable effective proliferation, providing a mechanism whereby age-induced ultrastructural changes in collagen and

关键词： aging collagen metastasis omentum ovarian cancer

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A Superoxide-Driven Redox State Promotes Geroconversion and Resistance to Senolysis in Replication-Stress Associated Senescence

SSRN

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SSRN 2023年

作者： Luo, Le Pervaiz, Shazib Clement, Marie-Veronique Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore117596 Singapore Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Singapore NUS Medicine Healthy Longevity Program National University of Singapore Singapore Integrated Science and Engineering Program NUS Graduate School National University of Singapore Singapore Yong Loo Lin School of Medicine National University of Singapore Singapore National University Cancer Institute National University Health System Singapore

Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we unravel the existence of a redox state associated with replication stress-induced senescence that we have coined senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe DCFH-DA. Moreover, measurement of GSH and GSSH reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Further supporting the key role of superoxide (O2.-) in the generation of SA-redox state, we show that incubation of senescent RPE1-hTERT with the O2.- scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidantś reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. Moreover, SA-redox state activates NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases the rate of TFEB protein synthesis, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and renders cells resistant to senolysis. However, SA-redox state does not prevent the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-βGal activity. Furthermore, while p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis. The latter is validated by the increased rate of p21 synthesis leading to p21 abundance upon the acquisition of SA-redox status, while maintaining low levels of p53 through an increase in the rate of p53 degradation despite buffering a decrease in p53 mRNA. © 2023, The Authors. All rights reserved.

关键词： Probes

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RETRACTION: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN (Retraction of Vol 28, Pg 271, 2010)

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NATURE BIOTECHNOLOGY 2022年第11期40卷 1692-1692页

作者： Foust, Kevin D. Wang, Xueyong McGovern, Vicki L. Braun, Lyndsey Bevan, Adam K. Haidet, Amanda M. Le, Thanh T. Morales, Pablo R. Rich, Mark M. Burghes, Arthur H. M. Kaspar, Brian K. Center for Gene Therapy The Research Institute at Nationwide Children’s Hospital Columbus Ohio USA Integrated Biomedical Graduate Program The Ohio State University Columbus Ohio USA Department of Molecular and Cellular Biochemistry The Ohio State University Columbus Ohio USA Wright State University Dayton Ohio USA The Mannheimer Foundation Inc. Homestead Florida USA

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Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

Nature Cancer

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Nature Cancer 2024年第3期5卷 400-419页

作者： Huang, Yu-Kai Cheng, Wei-Chung Kuo, Ting-Ting Yang, Juan-Cheng Wu, Yang-Chang Wu, Heng-Hsiung Lo, Chia-Chien Hsieh, Chih-Ying Wong, Sze-Ching Lu, Chih-Hao Wu, Wan-Ling Liu, Shih-Jen Li, Yi-Chuan Lin, Ching-Chan Shen, Chia-Ning Hung, Mien-Chie Lin, Jaw-Town Yeh, Chun-Chieh Sher, Yuh-Pyng Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Cancer Biology and Precision Therapeutics Center China Medical University Taichung Taiwan Ph.D. Program for Cancer Biology and Drug Discovery China Medical University and Academia Sinica Taichung Taiwan School of Chinese Medicine College of Chinese Medicine China Medical University Taichung Taiwan Graduate Institute of Integrated Medicine College of Chinese Medicine China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology College of Medical and Health Science Asia University Taichung Taiwan Center for Molecular Medicine China Medical University Hospital Taichung Taiwan Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Taipei Taiwan National Institute of Infectious Diseases and Vaccinology National Health Research Institutes Miaoli Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Biological Science and Technology China Medical University Taichung Taiwan Division of Hematology and Oncology China Medical University Hospital Taichung Taiwan Genomics Research Center Academia Sinica Taipei Taiwan Division of Gastroenterology and Hepatology Department of Internal Medicine E-Da Hospital Kaohsiung Taiwan Department of Medicine School of Medicine China Medical University Taichung Taiwan Department of Surgery Organ Transplantation Center China Medical University Hospital Taichung Taiwan Institute of Biochemistry and Molecular Biology China Medical University Taichung Taiwan

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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Core packing of well-defined x-ray and NMR structures is the same

arXiv

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arXiv 2022年

作者： Grigas, Alex T. Liu, Zhuoyi Regan, Lynne O’Hern, Corey S. Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Centre for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh United Kingdom Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

Numerous studies have investigated the differences and similarities between protein structures determined by solution NMR spectroscopy and those determined by x-ray crystallography. A fundamental question is whether any observed differences are due to differing methodologies, or to differences in the behavior of proteins in solution versus in the crystalline state. Here, we compare the properties of the hydrophobic cores of high-resolution protein crystal structures and those in NMR structures, determined using increasing numbers and types of restraints. Prior studies have reported that many NMR structures have denser cores compared to those of high-resolution x-ray crystal structures. Our current work investigates this result in more detail, and finds that these NMR structures tend to violate basic features of protein stereochemistry, such as small non-bonded atomic overlaps and few Ramachandran and side chain dihedral angle outliers. We find that NMR structures solved with more restraints, and which do not significantly violate stereochemistry, have hydrophobic cores that have a similar size and packing fraction as their counterparts determined by x-ray crystallography at high-resolution. These results lead us to conclude that, at least regarding the core packing properties, high-quality structures determined by NMR and x-ray crystallography are the same, and the differences reported earlier are most likely a consequence of methodology, rather than fundamental differences between the protein in the two different environments. Significance: Dense packing of hydrophobic residues is key to protein structure and stability. Previously, it has been noted that structures solved by NMR spectroscopy have denser cores than x-ray crystal structures. Here, we calculate the core size and packing fraction of NMR structures with experimental restraints in the PDB. Their cores are typically smaller, but denser. However, NMR structures with accurate stereochemistry possess core pa

关键词： X ray crystallography

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Uncovering diffusive states of the yeast proton pump, Pma1, and how labeling method can change diffusive behavior

arXiv

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arXiv 2022年

作者： Bailey, Mary Lou P. Pratt, Susan E. Zhang, Yongdeng Hinrichsen, Michael Bewersdorf, Joerg Regan, Lynne J. Mochrie, Simon G.J. Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06511 United States Department of Applied Physics Yale University New HavenCT06511 United States Department of Physics Yale University New HavenCT06511 United States Department of Cell Biology Yale University New HavenCT06511 United States Department of Biomedical Engineering Yale University New HavenCT06511 United States Institute of Quantitative Biology Biochemistry and Biotechnology Center for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Edinburgh06511 United Kingdom

We present and analyze video-microscopy-based single-particle-tracking measurements of the budding yeast (Saccharomyces cerevisiae) membrane protein, Pma1, fluorescently-labeled either by direct fusion to the switchable fluorescent protein, mEos3.2, or by a novel, light-touch, labeling scheme, in which a 5 amino acid tag is directly fused to the C-terminus of Pma1, which then binds mEos3.2. The diffusivity distributions of these two populations of single particle tracks differ significantly, demonstrating that labeling method can be an important determinant of diffusive behavior. We also applied perturbation expectation maximization (pEMv2) [Physical Review E 94, 052412 (2016)], which sorts trajectories into the statistically-optimum number of diffusive states. For both TRAP-labeled Pma1 and Pma1-mEos3.2, pEMv2 sorts the tracks into two diffusive states: an essentially immobile state and a more mobile state. However, the mobile fraction of Pma1-mEos3.2 tracks is much smaller (∼ 0.1) than the mobile fraction of TRAP-labeled Pma1 tracks (∼ 0.5). In addition, the diffusivity of Pma1-mEos3.2's mobile state is several times smaller than the diffusivity of TRAP-labeled Pma1's mobile state. To critically assess pEMv2's performance, we compare the diffusivity and covariance distributions of the experimental pEMv2-sorted populations to corresponding theoretical distributions, assuming that Pma1 displacements realize a Gaussian random process. The experiment-theory comparisons for both the TRAP-labeled Pma1 and Pma1-mEos3.2 reveal good agreement, bolstering the pEMv2 approach. © 2022, CC BY.

关键词： Diffusion

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Using physical features of protein core packing to distinguish real proteins from decoys

arXiv

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arXiv 2020年

作者： Grigas, Alex T. Mei, Zhe Treado, John D. Levine, Zachary A. Regan, Lynne O'Hern, Corey S. Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Department of Chemistry Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Pathology Yale University New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Centre for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

The ability to consistently distinguish real protein structures from computationally generated model decoys is not yet a solved problem. One route to distinguish real protein structures from decoys is to delineate the important physical features that specify a real protein. For example, it has long been appreciated that the hydrophobic cores of proteins contribute signifficantly to their stability. As a dataset of decoys to compare with real protein structures, we studied submissions to the bi-annual CASP competition (speciffically CASP11, 12, and 13), in which researchers attempt to predict the structure of a protein only knowing its amino acid sequence. Our analysis reveals that many of the submissions possess cores that do not recapitulate the features that define real proteins. In particular, the model structures appear more densely packed (because of energetically unfavorable atomic overlaps), contain too few residues in the core, and have improper distributions of hydrophobic residues throughout the structure. Based on these observations, we developed a deep learning method, which incorporates key physical features of protein cores, to predict how well a computational model recapitulates the real protein structure without knowledge of the structure of the target sequence. By identifying the important features of protein structure, our method is able to rank decoys from the CASP competitions equally well, if not better than, state-of-the-art methods that incorporate many additional features. Copyright © 2020, The Authors. All rights reserved.

关键词： Proteins

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